Lymphedema is a debilitating disease that may be caused by congenital disorder or acquired damage to lymphatic vessels. Patients with this disease manifest edematous swelling in the affected tissue because of excessive protein- and lipid-rich fluid in the interstitial space. Further tissue remodeling will result in adipose accumulation and fibrosis of the ailing tissue; treatment for this disease is so far limited. Recently, emerging studies have indicated that augmenting lymphangiogenesis, which results in generation of new lymphatic vessels, might represent a new therapeutic approach. Lymphangiogenesis is controlled by the VEGFC/VEGFR3 axis-induced proliferation and migration of lymphatic endothelial cells derived from the venous precursors. We recently demonstrated that apoA-I binding protein (AIBP) and caveolae/lipid rafts regulate angiogenesis. In this proposal, we sought to elucidate the role of AIBP and caveolae in lymphangiogenesis. Our preliminary studies suggest that AIBP and caveolae regulate VEGFR3 signaling and lymphangiogenesis. We will test the hypothesis that AIBP enhances VEGFR3 signaling by increasing cholesterol efflux and reducing the inhibition of caveolin-1 within caveolae. To this end, we will use in vitro lymphatic endothelial cell culture system, different transgenic zebrafish lines and genetically modified mouse models. Our studies on AIBP will contribute to the development of new therapies facilitating lymphatic vessel growth and restoring lymphatic functions in diseases caused by dysfunctional lymphatics.